An NMDA receptor is a postsynaptic, ionotropic receptor that is responsive to, inter alia, the excitatory amino acids glutamate and glycine and the synthetic compound NMDA. The NMDA receptor controls the flow of both divalent and monovalent ions into the postsynaptic neural cell through a receptor associated channel (Foster et al., Nature 1987, 329:395-396; Mayer et al., Trends in Pharmacol. Sci. 1990, 11:254-260). Activation of the NMDA receptor has been shown to be the central event which leads to excitotoxicity and neuronal death in many disease states, as well as a result of hypoxia and ischemia following head trauma, stroke and following cardiac arrest. The NMDA receptor has been implicated during development in specifying neuronal architecture and synaptic connectivity, and may be involved in experience-dependent synaptic modifications. In addition, NMDA receptors are also thought to be involved in long term potentiation and central nervous system disorders.
It is known in the art that the NMDA receptor plays a major role in the synaptic plasticity that underlies many higher cognitive functions, such as memory acquisition, retention and learning, as well as in certain nociceptive pathways and in the perception of pain (Collingridge et al., The NMDA Receptor, Oxford University Press, 1994). In addition, certain properties of NMDA receptors suggest that they may be involved in the information-processing in the brain that underlies consciousness itself.
NMDA receptor antagonists are therapeutically valuable for a number of reasons. In addition to anesthesia, certain NMDA receptor antagonists confer profound analgesia, a highly desirable component of general anesthesia and sedation. Also, NMDA receptor antagonists are neuroprotective under many clinically relevant circumstances (including neuropathic pain states, ischemia, brain trauma, and certain types of convulsions).
However, it is clear from the prior art that there are a number of drawbacks associated with current NMDA receptor antagonists. These include the production of involuntary movements, stimulation of the sympathetic nervous system, induction of neurotoxicity at high doses (which is pertinent since NMDA receptor antagonists have low potencies as general anesthetics), depression of the myocardium, and proconvulsions in some epileptogenic paradigms, e.g., “kindling” (Wlaz et al., Eur. J. Neurosci. 1994; 6:1710-1719). There have been considerable difficulties in developing new NMDA receptor antagonists that are able to cross the blood-brain barrier, which results in higher effective dosage requirements.
Commercially available NMDA antagonists have a wide variety of uses. For example, memantine provides rapid and enduring improvement in cognitive, psychological, social and motor impairments of dementia; dextromethorphan is used to relieve coughs; amantadine is an antiviral substance; and ketamine as an anesthetic agent. Certain opioids such as methadone, dextropropoxyphene, and ketobemidone are also classified as NMDA antagonists. MK-801 (dizocilpine maleate) and phencyclidine are not commercially used, and dextrophan, which is used commercially are other examples. However, a level of toxicity which accompanies these antagonists has proven to be problematic.
There are numerous potential commercial applications for NMDA antagonist formulations without neurotoxicity in supervised medical practice. Indications include, but are not limited to, treatment of dementia, suppression of cough (antitussive), antiviral treatment, treatment of involuntary muscle actions, antidepressant, suppression of addiction, and treatment of withdrawal. Ketamine, for example, can be used as an analgesic for breakthrough pain, anesthesia and sedation. Additional indications for ketamine include traumatic orthopedic injury pain, migraine pain, obstetrical use for end-stage labor pain, central pain, dental pain, and a host of additional conditions associated with acute and chronic, moderate to severe pain.
More specifically, ketamine, an NMDA receptor antagonist, has been in clinical use for over twenty-five years as a dissociative anesthetic and has demonstrated a wide margin of safety when used acutely as an anesthetic agent. Studies demonstrate the analgesic efficacy of ketamine in a variety of diverse indications including patient self-management of pain (U.S. Pat. Nos. 6,248,789 and No. 5,543,434 to Weg), post-operative analgesia (Naguib et al., Can. Anaesth. Soc. J. 1986, 33:16; Dich-Nielsen et al., Acta Anaesthesiol. Scand. 1992, 36:583; Battacharya et al., Ann. Acad. Med. Singapore 1994, 23:456), analgesia in emergency settings for patients suffering from fractures and soft tissue injury (Hirlinger and Pfenninger, Anaesthsist 1987, 36:140), musculoskeletal trauma (Gurnani et al., Anaesth. Intens. Care 1996, 24:32), wound care procedures (Bookwalter, Plastic Surg. Nursing 1994, 14:43; Humphries et al., J. Burn Care Rehabil. 1997, 18:34), management of acute episodes of neuropathic pain attributed to post-herpetic neuralgia (Eide et al., Pain 1994, 58:347), phantom limb pain (Knox et al., Anaesth. Intens. Care 1995, 23:620), nociceptive orofacial pain (Mathisen et al., Pain 1995, 61:215), and cancer pain (Mercadante et al., J. Pain Symptom Manage. 1995, 10:564; Clark and Kalan, J. Pain Symptom. Manage. 1995, 10:310; Fine, J. Pain Symptom Manage. 1999, 17:296; Lauretti et al., Anesthesiology 1999, 90:1528). These studies describe the use of ketamine administered by a variety of routes including transnasal, parenteral, and oral.
There are conflicting results from studies evaluating the potential for ketamine to cause neurotoxicity. Early in vitro studies examining the morphologic changes in cultured cells incubated with ketamine demonstrated that the drug induced, to a varied extent, damage of the myelin sheath and degeneration of mitochondria into multilamellar bodies in organotypic spinal cord slices derived from fetal rats (Shahar et al., Neurochem. Res. 1989, 14:1017). These apparent cytotoxic effects of ketamine were both dose-related and reversible. While no neurotoxic effects of ketamine have been observed in primates or rabbits, spinal cord lesions have been reported in rats and monkeys (Ahuja, Br. J. Anaesth. 1983, 55:991; Malinovsky et al., Anesthesiology 1991, 75:91; Gebhardt, Anaesthesist 1994, 43(suppl.2):S34). In addition, there is evidence of post-mortem histopathologic changes of subpial spinal cord vacuolation in a terminally ill cancer patient who received a continuous infusion of intrathecal ketamine at a rate of 5 mg/day for a duration of three weeks (Karpinski et al., Pain 1997, 73:103). Based on this finding, it was concluded that intrathecal ketamine may cause vacuolar myelopathy and that local vacuolation may be related to the lipophilicity of the drug. In addition, other studies have found that NMDA receptor antagonists, as phencycladine, MK-801, tiletamine, and ketamine cause neuronal vacuolization (Olney et al., Science 1989, 244:1360).
The studies describing the potential neurotoxic effects of ketamine are largely confined to administration of the drug by the intrathecal, or subarachnoid, route. Intrathecal administration of drugs may produce toxic reactions such as demyelination, arrachnoditis, and vascular changes and necrosis.
According to standard practice, ketamine is usually employed containing a preservative. Studies comparing the neurotoxicologic profile of preservative-free ketamine to ketamine containing preservative (chlorobutanol or benzethonium chloride) yielded curious results. Experiments with baboons, monkeys, rabbits, and rats receiving between 0.2 and 50 mg intrathecal ketamine with and without preservative failed to demonstrate histopathologic central nervous system lesions attributable to the drug, but nonetheless detected a breach of the blood brain barrier that was attributable to the presence of preservative (Malinovsky et al., Anesthesiology 1993, 78:109; Karpinski et al., Pain 1997, 73:103). The results were surprising since the combination of a drug with a preservative may also cause, or exacerbate, neurological damage due to the preservative itself (Brock-Utne et al., S.A. Med. J. 1982, 20:440). A further comparative study of multiple dose intrathecally administered preservative-free ketamine, ketamine containing the preservative benzethonium chloride, and benzethonium chloride alone was performed in an attempt to resolve the apparent discrepancies in the animal models (Errando et al., Reg. Anesth and Pain Med. 1999, 24:146). The results of this analysis demonstrated that preservative-free ketamine was without neurotoxic effect. However, ketamine with preservative produced minor changes to the spinal cord of the animals, and benzethonium chloride alone produced moderate neurotoxic effects (Errando et al., Reg. Anesth and Pain Med. 1999, 24:146). The results of this study confirm the lack of apparent independent neurotoxicity of ketamine and support the view that preservative-free ketamine is safe for intrathecal use in humans, even for repeated injections.
This observation was of limited value, however, since, while single-dose preparations may not require preservatives, other substances require the addition of preservatives to prevent or inhibit microbial growth and avoid spoilage of the preparation. Benzethonium chloride, a quaternary ammonium salt, is a common preservative similar to other cationic surfactants. The animal models, noted previously, indicated that the accompanying preservative, benzethonium chloride, and not ketamine itself, is the likely culprit mediating neurotoxicity in the anesthetic formulation following intrathecal administration of the drugs. With the known neurotoxic effects of this class of preservative, there remains a need in the art for a safe and effective analgesic and anesthetic formulation. The present invention addresses this need with a unique formulation which inhibits or diminishes the neurotoxicity.